The interplay between SUMOylation and phosphorylation of PKCδ facilitates oxidative stress‐induced apoptosis

Abstract

Although the increase in the number of identified posttranslational modifications (PTMs) has substantially improved our knowledge about substrate site specificity of single PTMs, the fact that different types of PTMs can crosstalk and act in concert to exert important regulatory mechanisms for protein function has not gained much attention. Here, we show that protein kinase Cδ (PKCδ) is SUMOylated at lysine 473 in its C‐terminal catalytic domain, and the SUMOylation increases PKCδ stability by repressing its ubiquitination. In addition, we uncover a functional interplay between the phosphorylation and SUMOylation of PKCδ, which can strengthen each other through recruiting SUMO E2/E3 ligases and the PKCδ kinase, respectively, to the PKCδ complexes. We identified PIAS2β as the SUMO E3 ligase of PKCδ. More importantly, by enhancing PKCδ protein stability and its phosphorylation through an interdependent interplay of the PTMs, the SUMOylation of PKCδ promotes apoptotic cell death induced by H2O2. We conclude that SUMOylation represents an important regulatory mechanism of PKCδ PTMs for the kinase's function in oxidative cell damage.

NUCLEAR PORE ANCHOR and EARLY IN SHORT DAYS 4 negatively regulate abscisic acid signaling by inhibiting Snf1‐related protein kinase2 activity and stability in Arabidopsis

“…ESD4 maintains SnRK2.6 in a low SUMOylation level, which may inhibit the interaction of SnRK2.6 with other kinases to decrease its phosphorylation; alternatively, the deSUMOylation of SnRK2.6 may affect its ubiquitination level which promotes its degradation mediated by 26S proteasome. Consistent with this notion, in mammalian cells, the SUMOylation and phosphorylation of protein kinase Cδ (PKCδ) act in concert to enhance the ability of this kinase to mediate the oxidative damage to cells (Gao et al, 2021). Inhibition of PKCδ phosphorylation decreased its affinity for the SUMO conjugating enzyme (UBC9) and/or SUMO ligase (PIAS2).…”

SUMOylation as a Therapeutic Target for Myocardial Infarction

“…SUMOylation of hyperphosphorylated tau at K340 inhibits its ubiquitylation and the subsequent proteasome-dependent degradation ( 39 ). Gao et al showed that PKCδ was SUMOylated at lysine 473, and the SUMOylation increased PKCδ stability by repressing its ubiquitination ( 40 ). Besides, SUMOylation induces conformational changes in proteins and thereby regulates protein functions ( 41 – 43 ).…”

SUMO wrestling in the cellular dohyō: crosstalk between phosphorylation and SUMOylation of PKCδ regulates oxidative cell damage

“…Based on the findings of Siman Gao and colleagues [6], a rather complex picture emerges as to how post‐translational modification of PKCδ regulates apoptosis (Fig. 1).…”

“…The interesting findings of Gao and colleagues [6] raise some intriguing questions for further investigation. Firstly, it would be useful to determine whether hydrogen peroxide does indeed mediate a SUMO and phosphorylation‐dependent cleavage of PKCδ.…”

“…This highlights the notion that cellular control over PKCδ function is essential for cell survival. In an interesting article published in this issue of The FEBS Journal, Siman Gao and colleagues [6] reveal another key player in the regulation of PKCδ – the modification by SUMOylation.…”